Randomised feasibility trial of a teaching assistant led extracurricular physical activity intervention for 9 to 11 year olds: Action 3:30

Background: Extracurricular programmes could provide a mechanism to increase the physical activity (PA) of primary-school-aged children. The aim of this feasibility study was to examine whether the Action 3:30 intervention, which is delivered by teaching assistants, holds promise as a means of increasing the PA of Year 5 and 6 children. Methods: A cluster randomised feasibility trial was conducted in 20 primary schools. Ten schools received the Action 3:30 intervention and 10 schools were allocated to the control arm. The intervention was 40 one-hour sessions, delivered twice a week by teaching assistants. The proportion of participants recruited per school was calculated. Session delivery and session attendance was calculated for intervention schools. Weekday and after-school (3.30 to 8.30 pm) moderate to vigorous intensity physical (MVPA) was assessed by accelerometer at baseline (T0), during the last few weeks of the intervention (T1) and four months after the intervention had ended (T2). The costs of delivering the intervention were estimated. Results: Five intervention schools ran all 40 of the intended sessions. Of the remaining five, three ran 39, one ran 38 and one ran 29 sessions. Mean attendance was 53%. The adjusted difference in weekday MVPA at T1 was 4.3 minutes (95% CI −2.6 to 11.3). Sex-stratified analyses indicated that boys obtained 8.6 more minutes of weekday MVPA than the control group (95% CI 2.8 to 14.5) at T1 with no effect for girls (0.15 minutes, 95% CI −9.7 to 10.0). There was no evidence that participation in the programme increased MVPA once the club sessions ceased (T2). The indicative average cost of this intervention was £2,425 per school or £81 per participating child during its first year and £1,461 per school or £49 per participating child thereafter. Conclusions: The effect of the Action 3:30 intervention was comparable to previous physical activity interventions but further analysis indicated that there was a marked sex difference with a positive impact on boys and no evidence of an effect on girls. The Action 3:30 intervention holds considerable promise but more work is needed to enhance the effectiveness of the intervention, particularly for girls

Applying an extended theoretical framework for data collection mode to health services research

<p>Abstract</p> <p>Background</p> <p>Over the last 30 years options for collecting self-reported data in health surveys and questionnaires have increased with technological advances. However, mode of data collection such as face-to-face interview or telephone interview can affect how individuals respond to questionnaires. This paper adapts a framework for understanding mode effects on response quality and applies it to a health research context.</p> <p>Discussion</p> <p>Data collection modes are distinguished by key features (whether the survey is self- or interviewer-administered, whether or not it is conducted by telephone, whether or not it is computerised, whether it is presented visually or aurally). Psychological appraisal of the survey request will initially entail factors such as the cognitive burden upon the respondent as well as more general considerations about participation. Subsequent psychological response processes will further determine how features of the data collection mode impact upon the quality of response provided. Additional antecedent factors which may further interact with the response generation process are also discussed. These include features of the construct being measured such as sensitivity, and of the respondent themselves (e.g. their socio-demographic characteristics). How features of this framework relate to health research is illustrated by example.</p> <p>Summary</p> <p>Mode features can affect response quality. Much existing evidence has a broad social sciences research base but is of importance to health research. Approaches to managing mode feature effects are discussed. Greater consideration must be given to how features of different data collection approaches affect response from participants in studies. Study reports should better clarify such features rather than rely upon global descriptions of data collection mode.</p

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Development, qualification, validation and application of the Ames test using a VITROCELL® VC10® smoke exposure system

The Ames test has established use in the assessment of potential mutagenicity of tobacco products but has generally been performed using partitioned exposures (e.g. total particulate matter [TPM], gas vapor phase [GVP]) rather than whole smoke (WS). The VITROCELL®VC10® smoke exposure system offers multiple platforms for air liquid interface (ALI), or air agar interface (AAI) in the case of the Ames test exposure to mimic in vivo-like conditions for assessing the toxicological impact of fresh WS in in vitro assays.The goals of this study were to 1) qualify the VITROCELL®VC10® to demonstrate functionality of the system, 2) develop and validate the Ames test following WS exposure with the VITROCELL®VC10® and 3) assess the ability of the Ames test to differentiate between a reference combustible product (3R4F Kentucky reference cigarette) and a primarily tobacco heating product (Eclipse). Based on critical function assessments, the VITROCELL®VC10® was demonstrated to be fit for the purpose of consistent generation of WS. Assay validation was conducted for 5 bacterial strains (TA97, TA98, TA100, TA1535 and TA102) and reproducible exposure–related changes in revertants were observed for TA98 and TA100 in the presence of rat liver S-9 following exposure to 3R4F WS. In the comparative studies, exposure-related changes in in vitro mutagenicity following exposure of TA98 and TA100 in the presence of S9 to both 3R4F and Eclipse WS were observed, with the response for Eclipse being significantly less than that for 3R4F (p < 0.001) which is consistent with the fewer chemical constituents liberated by primarily-heating the product. Keywords: Whole smoke, Smoke exposure system, Ames test, 3R4F, Eclipse, Mutagenicity, Tobacco heating produc

Acute Toxicities of the Saxitoxin Congeners Gonyautoxin 5, Gonyautoxin 6, Decarbamoyl Gonyautoxin 2&amp;3, Decarbamoyl Neosaxitoxin, C-1&amp;2 and C-3&amp;4 to Mice by Various Routes of Administration

Paralytic shellfish poisoning results from consumption of seafood naturally contaminated by saxitoxin and its congeners, the paralytic shellfish toxins (PSTs). The levels of such toxins are regulated internationally, and maximum permitted concentrations in seafood have been established in many countries. A mouse bioassay is an approved method for estimating the levels of PSTs in seafood, but this is now being superseded in many countries by instrumental methods of analysis. Such analyses provide data on the levels of many PSTs in seafood, but for risk assessment, knowledge of the relative toxicities of the congeners is required. These are expressed as “Toxicity Equivalence Factors” (TEFs). At present, TEFs are largely based on relative specific activities following intraperitoneal injection in a mouse bioassay rather than on acute toxicity determinations. A more relevant parameter for comparison would be median lethal doses via oral administration, since this is the route through which humans are exposed to PSTs. In the present study, the median lethal doses of gonyautoxin 5, gonyautoxin 6, decarbamoyl neosaxitoxin and of equilibrium mixtures of decarbamoyl gonyautoxins 2&amp;3, C1&amp;2 and C3&amp;4 by oral administration to mice have been determined and compared with toxicities via intraperitoneal injection. The results indicate that the TEFs of several of these substances require revision in order to more accurately reflect the risk these toxins present to human health